title: CXCR4 chemokine receptor signaling induces apoptosis in acute myeloid leukemia cells via regulation of the Bcl-2 family members Bcl-XL, Noxa, and Bak.
abstract: The CXCR4 chemokine receptor promotes survival of many different cell types. Here, we describe a previously unsuspected role for CXCR4 as a potent inducer of apoptosis in acute myeloid leukemia (AML) cell lines and a subset of clinical AML samples. We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4, but ERK activation did not lead to survival. Instead, SDF-1 treatment led via a CXCR4-dependent mechanism to apoptosis, as evidenced by increased annexin V staining, condensation of chromatin, and cleavage of both procaspase-3 and PARP. This SDF-1-induced death pathway was partially inhibited by hypoxia, which is often found in the bone marrow of AML patients. SDF-1-induced apoptosis was inhibited by dominant negative procaspase-9 but not by inhibition of caspase-8 activation, implicating the intrinsic apoptotic pathway. Further analysis showed that this pathway was activated by multiple mechanisms, including up-regulation of Bak at the level of mRNA and protein, stabilization of the Bak activator Noxa, and down-regulation of antiapoptotic Bcl-XL. Furthermore, adjusting expression levels of Bak, Bcl-XL, or Noxa individually altered the level of apoptosis in AML cells, suggesting that the combined modulation of these family members by SDF-1 coordinates their interplay to produce apoptosis. Thus, rather than mediating survival, SDF-1 may be a means to induce apoptosis of CXCR4-expressing AML cells directly in the SDF-1-rich bone marrow microenvironment if the survival cues of the bone marrow are disrupted.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Kremer
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: X Wei
authors.initials: XW
authors.lastname: Meng
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Christie
authors.initials: C
authors.lastname: Rodriguez-Ramirez
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hedin
mesh_terms: D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002470:Cell Survival / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D055550:Protein Stability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis* / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D017304:Annexin A5; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
keywords: AML; Apoptosis; Bcl-2 Family Proteins; CXCL12; CXCR4; Cancer; Caspase; Chemokines; Leukemia; SDF-1